The genetics of the Rhesus blood group system.

The Rhesus factor is clinically the most important protein-based blood group system. With 49 antigens so far described, it is the largest of all 29 blood group systems. The unusually large number of Rhesus antigens is attributable to its complex genetic basis. The antigens are located on two Rhesus proteins - RhD and RhCE - and are produced by differences in their protein sequences. In CD nomenclature, they are termed CD240D and CD240CE. Unlike proteins of other blood groups, Rhesus proteins are expressed only in the membranes of red blood cells and their immediate precursors1. Rhesus is second in its clinical importance only to the ABO blood group. Since the introduction of postpartum anti-D prophylaxis in the late 1960s, and combined pre-and postpartum anti-D prophylaxis in the early 1990s, the incidence of haemolytic disease in newborns due to alloimmunization has been reduced by more than 90%. Up to 1% of all pregnant women have clinically significant anti-erythrocyte antibodies2,3. Anti-D remains the main indication for phototherapy or exchange transfusions in newborns2,4, and pregnant women who are D negative show an above average incidence. The five most important Rhesus antigens are the cause of most alloimmunizations following blood transfusion. According to the German haemotherapy guidelines [Richtlinien zur Gewinnung von Blut und Blutbestandteilen und zur Anwendung von Blutprodukten]5, D negative transfusion recipients must always be given D negative erythrocyte products. Since 2000, women of reproductive age and girls have also received transfusions compatible for further Rhesus antigens such as C, c, E and e in addition to the K antigen of the Kell blood group5. This procedure also applies to patients who receive regular transfusions or have immunohaematological problems, like anti-erythrocyte allo- and autoantibodies. In the case of autoantibodies, their exact specificity is not usually determined. Although one thirds of such autoantibodies are directed at Rhesus proteins, this has virtually no practical consequences for treatment1. The D antigen, discovered in 1939, was the first Rhesus antigen to be described. D positive patients were termed Rhesus-positive. In 1946, a quantitative variant with a weakly expressed D antigen was discovered and termed “Du”. This variant, now called “weak D”, is of clinical and diagnostic importance. Since 1953, is has been clear that there are also qualitative variants of the D antigen. Although patients with this partial D variant are positive for the D antigen, they can also form anti-D.